Epigenetic mechanisms linking psychosocial stress with coronary heart disease

项目摘要 社会心理压力的升高--现代快节奏社会的一个标志--一再被认为与 免疫功能改变和冠心病（CHD）风险增加，但其机制 这些关联尚不清楚。DNA甲基化，一个关键的和研究最多的表观遗传过程， 人类，已成为环境暴露与人类健康之间的一个关键环节。我们的长期 目的是阐明心理社会压力通过表观遗传和其他分子机制 会导致动脉粥样硬化本申请的总体目标是定义甲基化组学。 在全血和不同的免疫细胞类型中与应激相关的差异，并确定如何 这些差异可以影响免疫功能并预测CHD风险。核心假设是压力 驱动甲基化模式，表观遗传上调促炎和其他免疫介质， 不同的血细胞类型，从而导致CHD的发生。这一应用的基本原理是， 外周血免疫细胞中与应激相关的表观基因组模式及其功能后遗症可以产生 新的复合预测因子和分子靶点，可用于加强CHD预防， 治疗将通过结合人类队列中的大规模分析来检验中心假设， 细胞模型中的机制研究。将追求三个不同但互补的具体目标： 确定全血中预测CHD事件的应激相关甲基化谱; 2）定义细胞类型- 与压力相关并预测CHD的特定甲基化模式;和3）机械地剖析 应激如何在表观遗传学上调节培养单核细胞功能。目标1和2将利用多个大型队列 参与NHLBI精准医学Trans-Omics（TOPMed）计划的研究， 心理社会应激、全血DNA甲基化和/或偶发CHD数据。细胞类型特异性甲基化 模式将使用该研究最近开发的尖端计算方法进行解卷积 团队关键的表观遗传信号将使用单核细胞和单核细胞的细胞模型进行机械解剖， 暴露于生理水平的应激激素和靶向DNA的衍生巨噬细胞 甲基化编辑。这一跨学科的建议是创新的，因为它将整合大规模的 在多个TOPMed研究中应用新的计算方法， 免疫细胞模型中的机械工作。这项研究具有重要意义，因为它有望产生创新的成果。 表观遗传预测因子和可操作的分子靶点，可用于加强预防和 压力相关冠心病的治疗。

PROJECT SUMMARY Elevated psychosocial stress – a hallmark of modern, fast-paced societies – has been repeatedly associated with altered immune function and increased coronary heart disease (CHD) risk, but the mechanisms underlying these associations are unclear. DNA methylation, one of the critical and most studied epigenetic processes in humans, has emerged as a key link between environmental exposures and human health. Our long-term goal is to elucidate the epigenetic and other molecular mechanisms through which psychosocial stress contributes to atherosclerotic disease. The overall objective of this application is to define the methylomic differences associated with stress both in whole blood and in distinct immune cell types and to determine how these differences can shape immune function and predict CHD risk. The central hypothesis is that stress drives methylomic patterns that epigenetically upregulate proinflammatory and other immune mediators across distinct blood cell types, thereby contributing to incident CHD. The rationale for this application is that determining stress-associated epigenomic patterns and their functional sequelae in peripheral blood immune cells can yield novel composite predictors and molecular targets that can be leveraged to enhance CHD prevention and treatment. The central hypothesis will be tested by combining large-scale analyses in human cohorts and mechanistic investigations in cell models. Three distinct but complementary specific aims will be pursued: 1) Identify stress-associated methylomic profiles in whole blood that predict incident CHD; 2) Define cell type- specific methylomic patterns that are associated with stress and predict CHD; and 3) Mechanistically dissect how stress epigenetically regulates monocyte function in culture. Aims 1 and 2 will leverage multiple large cohort studies that participate in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and have suitable psychosocial stress, whole-blood DNA methylation, and/or incident CHD data. Cell type-specific methylomic patterns will be deconvoluted using cutting-edge computational methods recently developed by the research team. Key epigenetic signals will be mechanistically dissected using cell models of monocytes and monocyte- derived macrophages undergoing exposure to physiological levels of stress hormones and targeted DNA methylation editing in culture. This interdisciplinary proposal is innovative as it will integrate large-scale association efforts that apply novel computational methods across multiple TOPMed studies with cutting-edge mechanistic work in immune cell models. The proposed research is significant as it is expected to yield innovative epigenetic predictors and actionable molecular targets that can be leveraged to enhance prevention and treatment of stress-associated CHD.